Nature, 525, 87-90 - Chemistry Labs - Princeton University
LETTER
doi:10.1038/nature14885
Alcohols as alkylating agents in heteroarene C–H functionalization Jian Jin1 & David W. C. MacMillan1
Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage1. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of ‘spin-centre shift’2, during which an alcohol C–O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radicalbased alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides3–7, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone. During DNA biosynthesis, ribonucleoside diphosphates are converted into their deoxyribonucleoside equivalents via the enzymatic activity of ribonucleotide reductase (class I–III)8. Crucially, a (39,29)spin-centre shift occurs, resulting in b-C–O scission and elimination of water (Fig. 1a). Considering the efficiency of this mild enzymatic process to cleave C–O bonds to generate transient radicals, we postulated whether an analogous chemical process could occur with simple alcohols, such as methanol, to access radical intermediates for use in challenging bond constructions (Fig. 1b). In the medicinal chemistry community, there is growing demand for the direct introduction of alkyl groups, especially methyl groups, to heteroarenes, given their influence on drug metabolism and pharmacokinetic profiles9. The open-shell addition of alkyl radical intermediates to heteroarenes, known as the Minisci reaction10, has become a mainstay transformation with broad application within modern drug discovery11. Unfortunately, many current methods are limited in their application to late-stage functionalization of complex molecules owing to their dependence on the use of strong stoichiometric oxidants or increased temperatures to generate the requisite alkyl radicals3–6. A photoredox-catalysed alkylation protocol using peroxides as the alkyl radical precursors was recently demonstrated7. Given the state of the art, we questioned whether a general alkylation protocol could be devised in which a broad range of substituents could be installed from simple commercial alcohols under mild conditions. Visible light-mediated photoredox catalysis has emerged in recent years as a powerful technique in organic synthesis that facilitates single-electron transfer events with organic substrates12–14. This general strategy allows for the development of bond constructions that are often elusive or currently impossible via classical two-electron 1
pathways. Recently, our laboratory introduced a new dual photoredoxorganocatalytic platform to enable the functionalization of unactivated sp3 C2H bonds15–17. This catalytic manifold provides access to radical intermediates via C2H abstraction, resulting in the construction of challenging C2C bonds via a radical–radical coupling mechanism. With the insight gained from this dual catalytic system and our recent work on the development of a photoredox-catalysed Minisci reaction18, we questioned whether it would be possible to generate alkyl radicals from alcohols and use them as alkylating agents in a heteroaromatic C–H functionalization reaction (Fig. 1c). While there are a few early reports of alcohols as alkyl radical precursors formed via high-energy irradiation (ultraviolet light and gamma rays)19–21, a general and robust strategy for using alcohols as latent alkylating agents has been elusive. This transformation would represent a direct C2H alkylation of heteroaromatics with alcohols via a spin-centre shift pathway, eliminating H2O as the only by-product. We recognized that this mild alkylating procedure would serve as a powerful and general method in late-stage functionalization, using commercially available and abundant alcohols as latent alkylating agents. A detailed description of our proposed dual catalytic mechanism for the alkylation of heteroarenes with alcohols is outlined in Fig. 2. Irradiation of Ir(ppy)2(dtbbpy)1 (1) (in which ppy 5 2-phenylpyridine, dtbbpy 5 4,49-di-tert-butyl-2,29-bipyridine) will generate the longa PPO
PPO
R
R
O HO
O OH
O
RNR class I
SCS
–H2O
b
H
H
H
HO C H
H H
c
Photoredox R
HO Me
R N
Methanol
H
Organocatalysis
N
–H2O
Methyl adduct
Heteroarene R
SCS
N H
OH
Me
R N H
Figure 1 | Bio-inspired alkylation process using alcohols as spin-centre shift equivalents via a dual catalytic platform. a, DNA biosynthesis occurs via a spin-centre shift (SCS) process, catalysed by ribonucleotide reductase (RNR) class I to generate a carbon-centred radical, after elimination of H2O as a byproduct. b, Alcohols (for example, methanol) as radical intermediates when spin-centre shift allowed. c, Proposed direct installation of alkyl groups using alcohols under mild photoredox organocatalytic conditions.
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RESEARCH LETTER
R
R
N Me
N
11
Methylated heteroarene 12
R
R
NH
SCS
NH
–H+
–H2O
10
9
OH
OH
+ H+ R
SET
NH
Heteroarene 3 IrIV (4) oxidant
*IrIII (2) reductant
OH
Photoredox catalytic cycle
SH
EtO SET
cat. 5
IrIII (1) Photoredox catalyst
Visible light source
8
O
Organocatalytic
Me
HAT
cycle PF6–
O
t-Bu
N N N
t-Bu
Ir N
Ir(ppy)2(dtbbpy)PF6 (1)
S
EtO 6
Me
MeOH Alcohol 7
Methanol as methylating agent
Figure 2 | Proposed mechanism for the direct alkylation of heteroaromatic C–H bonds via photoredox organocatalysis. The catalytic cycle is initiated via excitation of photocatalyst 1 to give the excited state 2. A sacrificial amount of heteroarene 3 oxidizes *IrIII 2 to IrIV 4, which then oxidizes thiol catalyst 5 to generate thiyl radical 6 and regenerate catalyst 1. Thiyl radical 6 then abstracts a hydrogen atom from alcohol 7 to form a-oxy radical 8. Radical 8 adds to heteroarene 3, producing radical cation 9, which after deprotonation forms a-amino radical 10. Spin-centre shift elimination of H2O forms radical intermediate 11. Protonation and reduction by *IrIII 2 delivers alkylated product 12. HAT, hydrogen atom transfer; MeOH, methanol; SET, singleelectron transfer.
lived *Ir(ppy)2(dtbbpy)1 (2) excited state (t 5 557 ns)22. As *Ir(ppy)2(dtbbpy)1 (2) can function as either a reductant or an oxidant, we postulated that 2 would undergo a single-electron transfer event with a sacrificial quantity of protonated heteroarene 3 to initiate the first catalytic cycle and provide the oxidizing Ir(ppy)2(dtbbpy)21 (4). Given the established oxidation potential of Ir(ppy)2(dtbbpy)21 (4) (E1/2red 5 11.21 V versus saturated calomel electrode in CH3CN)22, we anticipated that single-electron transfer from the thiol catalyst 5 (E1/2red 5 10.85 V versus saturated calomel electrode for cysteine)23 to Ir(ppy)2(dtbbpy)21 (4) would occur and, after deprotonation, furnish the thiyl radical 6 while returning Ir(ppy)2(dtbbpy)1 (1) to the catalytic cycle. At this stage, we presumed that the thiyl radical 6 would undergo hydrogen atom transfer with the alcohol 7 (a comparable thiol, methyl 2-mercaptoacetate S–H bond dissociation energy 5 87 kcal mol21 (ref. 24), methanol a-C–H bond dissociation energy 5 96 kcal mol21 (ref. 25)) to provide the a-oxy radical 8 and regenerate the thiol catalyst 5, driven by the polar effect in the transition state26. The polar effect is a remarkable property that enables considerably endergonic C–H abstractions that would not be possible otherwise27. The nucleophilic a-oxy radical 8 would then add to the protonated electrondeficient heteroarene 3 in a Minisci-type pathway to afford the aminyl radical cation 9. The resulting a-C–H bond of 9 is sufficiently acidic to undergo deprotonation to form the a-amino radical 10 (ref. 28). At this juncture, intermediate 10 is primed to undergo a spin-centre shift to eliminate H2O and generate benzylic radical 11. The resulting openshell species would then undergo protonation followed by a second
single-electron transfer event with the excited photocatalyst 2 to regenerate the active oxidant Ir(ppy)2(dtbbpy)21 (4), while providing the desired alkylation product 12. We first examined this new alkylation protocol using isoquinoline and methanol as the coupling partners, and evaluated a range of photocatalysts and thiol catalysts. Using Ir(ppy)2(dtbbpy)PF6 (1) and ethyl 2-mercaptopropionate (5), along with p-toluenesulfonic acid and blue light-emitting diodes as the light source, we were able to achieve the desired C–C coupling to provide 1-methylisoquinoline (15) with a 92% yield (see Supplementary Information). Notably, we observed none of the desired product in the absence of photocatalyst, thiol catalyst, acid or light, demonstrating the requirement of all components in this dual catalytic protocol. In addition, this method requires only weak visible light and ambient temperature to install methyl substituents using methanol as the alkylating agent. With the optimal conditions in hand, we sought to evaluate the generality of this dual catalytic alkylation transformation. As highlighted in Fig. 3a, a wide range of heteroaromatics are methylated under the reaction conditions. Isoquinolines with electron-donating or -withdrawing substituents (such as methyl substituents, esters and halides) are functionalized in excellent efficiencies (15–18, 85–98% yield). Quinolines perform effectively, including those that contain non-participating functionality (19–23, 65–95% yield), in addition to phthalazine and phenanthridine coupling partners (24 and 25, 70% and 93% yield). Moreover, a wide range of pyridine derivatives containing diverse functionality (such as esters, amides, arenes, nitriles and trifluoromethyl groups) can be converted into the desired methylation products in high yield (26–32, 65–91% yield). Next, we sought to investigate the nature of the alcohol coupling partner, as demonstrated in Fig. 3b. A broad array of primary alcohols can effectively serve as alkylating agents in this new alkylation reaction. In contrast to the methylation conditions highlighted above, alcohols in Fig. 3b typically use methyl thioglycolate 13 as the C–H abstraction catalyst. Notably, simple aliphatic alcohols such as ethanol and propanol deliver the alkylated isoquinoline product in high yields (33 and 34, 95% and 96% yield). Steric bulk proximal to the alcohol functionality is tolerated, as exemplified by the presence of isopropyl, b-tetrahydropyran, b-aryl and b-adamantyl substituents (35–38, 87– 92% yield). The presence of an electron-withdrawing trifluoromethyl (CF3) group distal to the alcohol decreases the rate of the reaction; however, using the more electrophilic thiol catalyst, 2,2,2-trifluoroethanethiol (14), can promote the transformation more efficiently, possibly owing to the polar effect on the hydrogen atom transfer transition state (39, 93% yield)26. We found that diols also participate readily in this alkylation protocol (40 and 41, 88% and 81% yield). It should be noted that 1,3-butanediol demonstrates exceptional chemoselectivity and undergoes alkylation exclusively at the primary alcohol site. We speculate that the corresponding a-oxy radical at the secondary alcohol position does not attack the protonated heteroarene owing to its increased steric hindrance. For these alkylating agents with several reactive sites (41, 43 and 44), thiol catalyst 5 is the most effective hydrogen atom transfer catalyst—mechanistic studies are continuing to determine the origin of these differences in catalyst reactivity. Ethers, in the form of differentially substituted tetrahydrofurans, are also competent alkylating agents in this dual catalytic platform (42–44, 72–90% yield). In the elimination step, the tetrahydrofuran ring opens to reveal a pendent hydroxyl group. Interestingly, 3-hydroxytetrahydrofuran and tetrahydrofurfuryl alcohol react regioselectively at the ether a-oxy site distal to the alcohol to afford alkylation products with terminal pinacol motifs. We attribute this exclusive regioselectivity to a subtle influence on C–H bond dissociation energy owing to the inductive influence of the oxygen atoms. The application of these substrates represents an effective method to install vicinal diol motifs that would be inaccessible using traditional oxidative alkylation methods. Finally, the utility of this mild alkylation protocol has been demonstrated by the late-stage
2 | N AT U R E | VO L 0 0 0 | 0 0 M O N T H 2 0 1 5 G2015
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LETTER RESEARCH 1 mol% photocatalyst 1 R1
HO N
H
O
5 mol% thiol catalyst 5
R2
R1
TsOH, DMSO, Blue LEDs, 23 °C
Heteroarene
R2
N
Thiol cat. 5
F3C
SH
MeO
Me
Alkylated heteroarene
Alcohol
O
SH
EtO
Thiol cat. 13
SH
Thiol cat. 14
a Heteroarenes Me N
N
Me
Me N
Me
16, 91% yield
Me
Me
N
Me
15, 92% yield
Br
CO 2Me
N
Me
17, 98% yield
18, 85% yield
Me
Me
Me
N
21, 93% yield
N
Me
23, 89% yield
Me
CO 2Me
27, 81% yield
Me
b Alcohol
N
26, 82% yield Me
CF 3
CN
Me
N
N
Product
N
Me
N
29a: 2-Me, 65% yield 29b: 2,6-diMe, 12% yield
28, 83% yield
CO 2Me Me
Ph
Ph N
Me
25, 93% yield
24, 70% yield
CONH 2 Me
Me N
Me
Me
Me
20, 95% yield
N
Ph
22, 91% yield
19a: 2-Me, 43% yield 19b: 4-Me, 22% yield
N
Br
N
N
c
Product
Alcohol
Me
Me
31a: 2-Me, 56% yield 30a: 4-Me, 61% yield 30b: 2-Me, 15% yield 31b: 2,6-diMe, 25% yield 30c: 2,4-diMe, 7% yield
N
Me
32, 91% yield
Product
Ether R
HO
N
R
N
N
HO R
33 R = Me 34 R = Et
95% yield 96% yield
N
O Me
Me
OH
90% yield 72% yield
42 R = H 43 R = OH
35, 91% yield
Me
HO
N
N
O
O
HO
OH
OH
44, 77% yield
Me
36, 87% yield
R
O
OH
37, 90% yield
d Medicinal agents N
HO
CF 3
HN
N
HO
CF 3
N
39, 93% yield
38, 92% yield
O
S
N
O
CN
HO
OH
N
OH
HO
N
N OH Me
OH
40, 88% yield
Me
N H
O
Me
Me
Fasudil derivative
41, 81% yield
45, 82% yield
Milrinone derivative 46, 43% yield
Figure 3 | Substrate scope for the alkylation of heteroaromatic C–H bonds with alcohols via the dual photoredox organocatalytic platform. A broad range of heteroaromatics and alcohols are efficiently coupled to produce alkylated heterocycles under the standard reaction conditions (top, generalized reaction). a, A variety of isoquinolines, quinolines, phthalazines, phenanthridines and pyridines are efficiently methylated using methanol as the alkylating reagent. b, A diverse selection of alcohols serve as effective alkylating
agents in this dual catalytic protocol. c, Ethers are also amenable to the transformation; the products are the corresponding ring-opened alcohols. d, Two pharmaceuticals, fasudil and milrinone, can be alkylated using this protocol, demonstrating its utility in late-stage functionalization. Isolated yields are indicated below each entry. See Supplementary Information for experimental details.
functionalization of several pharmaceutical compounds. Using methanol as a simple methylating agent, fasudil, a potent Rho-associated protein kinase inhibitor and vasodilator, can be methylated in 82% yield (product 45). Additionally, milrinone, a phosphodiesterase 3 inhibitor and vasodilator, can be alkylated with 3-phenylpropanol in 43% yield (product 46). Mechanistic studies have been conducted to support the proposed pathway outlined in Fig. 2. Stern–Volmer fluorescence quenching experiments have demonstrated that the *IrIII excited state 2 is
quenched in the presence of protonated heteroarene 3, but not in the presence of the unprotonated heteroarene or thiol catalyst 5, indicating an oxidative quenching pathway (see Supplementary Information). Furthermore, a series of experiments were conducted to investigate the proposed spin-centre shift elimination. After exposing hydroxylated intermediate 47 to the reaction conditions, only a modest amount of the methylated isoquinoline 15 is observed (8% yield, entry 1, Fig. 4a). In the absence of an acid additive, only trace yields of the desired product are formed (2% yield, entry 2, Fig. 4a). However, in 0 0 M O N T H 2 0 1 5 | VO L 0 0 0 | N AT U R E | 3
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RESEARCH LETTER a
2.
1 mol% photocatalyst 1 N
N
3.
2 eq. reductant, 2 eq. acid
47
DMSO, blue LEDs, 23 °C
OH
Entry
Light
Photocatalyst
1
Yes
Yes
2
Yes
3
15
Me
4.
Reductant
Acid
Yield
None Bu3N-HCO2H
TsOH
8%
Yes
None
2%
Yes
Yes
Bu3N-HCO2H
TsOH
60%
4
No
Yes
Bu3N-HCO2H
TsOH
0%
5
Yes
No
Bu3N-HCO2H
TsOH
0%
5. 6.
7.
8.
b
+ e–
N
47 48
N
H
+ e– H
15
9.
49
OH
SCS cleaves alcohol C–O bond
c
1 mol% photocat. 1 N
10.
N
2 eq. TsOH, DMSO
47
OH
blue LEDs, 23 °C
11. 12.
50 65% yield
Figure 4 | Mechanistic studies support spin-centre shift elimination pathway. a, Hydroxymethyl intermediate 47 can be converted to methylated 15 under net reductive conditions after addition of formic acid-tributylamine and p-toluenesulfonic acid (TsOH). b, Deoxygenation of 47 probably proceeds via a spin-centre shift pathway to cleave the alcohol C–O bond. c, In the presence of styrene, 47 is converted to 50, presumably by trapping of radical 49. DMSO, dimethylsulfoxide; LEDs, light-emitting diodes.
13.
14. 15.
16.
17.
Wessig, P. & Muehling, O. Spin-center shift (SCS) – a versatile concept in biological and synthetic chemistry. Eur. J. Org. Chem. 2219–2232 (2007). Minisci, F., Vismara, E. & Fontana, F. Homolytic alkylation of protonated heteroaromatic bases by alkyl iodides, hydrogen peroxide, and dimethyl sulfoxide. J. Org. Chem. 54, 5224–5227 (1989). Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011). Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011). Antonchick, A. P. & Burgmann, L. Direct selective oxidative cross-coupling of simple alkanes with heteroarenes. Angew. Chem. Int. Edn Engl. 52, 3267–3271 (2013). DiRocco, D. A. et al. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Edn Engl. 53, 4802–4806 (2014). Eklund, H., Uhlin, U., Fa¨rnega˚rdh, M., Logan, D. T. & Nordlund, P. Structure and function of the radical enzyme ribonucleotide reductase. Prog. Biophys. Mol. Biol. 77, 177–268 (2001). Scho¨nherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Edn Engl. 52, 12256–12267 (2013). Minisci, F., Bernardi, R., Bertini, F., Galli, R. & Perchinunno, M. Nucleophilic character of alkyl radicals–VI: A new convenient selective alkylation of heteroaromatic bases. Tetrahedron 27, 3575–3579 (1971). Duncton, M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal chemists. Med. Chem. Commun. 2, 1135–1161 (2011). Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011). Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013). Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014). Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014). Hager, D. & MacMillan, D. W. C. Activation of C–H bonds via the merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. J. Am. Chem. Soc. 136, 16986–16989 (2014). Cuthbertson, J. D. & MacMillan, D. W. C. The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015). Jin, J. & MacMillan, D. W. C. Direct a-arylation of ethers through the combination of photoredox-mediated C–H functionalization and the Minisci reaction. Angew. Chem. Int. Edn Engl. 54, 1565–1569 (2015). Ochiai, M. & Morita, K. A novel photo-induced methylation of pyrimidines and condensed pyrimidine compounds. Tetrahedr. Lett. 8, 2349–2351 (1967). Stermitz, F. R., Wei, C. C. & Huang, W. H. Imine photoalkylations: quinolone and isoquinoline. Chem. Commun. (Lond.) 1968, 482–483 (1968). Sugimori, A. et al. Radiation-induced alkylation of quinoline derivatives with alcohol. Bull. Chem. Soc. Jpn. 59, 3905–3909 (1986). Slinker, J. D. et al. Efficient yellow electroluminescence from a single layer of a cyclometalated iridium complex. J. Am. Chem. Soc. 126, 2763–2767 (2004). Shaidarova, L. G., Ziganshina, S. A. & Budnikov, G. K. Electrocatalytic oxidation of cysteine and cystine at a carbon-paste electrode modified with ruthenium(IV) oxide. J. Anal. Chem. 58, 577–582 (2003). Escoubet, S. et al. Thiyl radical mediated racemization of nonactivated aliphatic amines. J. Org. Chem. 71, 7288–7292 (2006). Berkowitz, J., Ellison, G. B. & Gutman, D. Three methods to measure RH bond energies. J. Phys. Chem. 98, 2744–2765 (1994). Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999). Cai, Y. & Roberts, B. P. Radical-chain racemization of tetrahydrofurfuryl acetate under conditions of polarity-reversal catalysis: possible implications for the radical-induced strand cleavage of DNA. Chem. Commun. (Camb.) 1998, 1145–1146 (1998). McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an a-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).
the presence of a stoichiometric reductant and p-toluenesulfonic acid, the elimination of oxygen can be achieved in good efficiency (60% yield, entry 3, Fig. 4a). Crucially, this elimination pathway is shut down in the absence of either light or photocatalyst (entry 4 or 5, respectively, Fig. 4a). Therefore, this net reductive process supports the proposed generation of a-amino radical 48, which could readily form deoxygenated product 15 via a spin-centre shift pathway to b-amino radical 49 (Fig. 4b). This elimination pathway is further corroborated by a series of radical trapping experiments (Fig. 4c and Supplementary Information). In the presence of styrene, hydroxymethyl arene 47 is transformed to adduct 50 (65% yield, Fig. 4c), presumably via the intermediacy of b-amino radical 49. Finally, while we support the mechanism outlined in Fig. 2, we cannot rule out the possibility of a radical chain pathway in which radical 11 abstracts an H-atom from alcohol 7 or thiol catalyst 5. In summary, this alkylation strategy represents the first, to our knowledge, general use of alcohols as simple alkylating agents and enables rapid late-stage derivatization of medicinally relevant molecules. Given the influence on drug pharmacokinetics and absorption, distribution, metabolism and excretion (ADME) properties, this method of installing inert alkyl groups will probably find wide application in the medicinal chemistry community. We have developed a mild and operationally simple alkylation reaction via the synergistic merger of photoredox and thiol hydrogen atom transfer organocatalysis to forge challenging heteroaryl C–C bonds using alcohols as latent nucleophiles. This bio-inspired strategy mimics the key step in enzyme-catalysed DNA biosynthesis via a new spin-centre shift elimination of H2O to generate radical intermediates from simple alcohols.
18.
Received 20 May; accepted 26 June 2015.
Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to D.W.C.M. ([email protected]).
Published online 26 August 2015. 1.
Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 4th edn (Oxford Univ. Press, 2007).
19. 20. 21. 22. 23.
24. 25. 26.
27.
28.
Supplementary Information is available in the online version of the paper. Acknowledgements Financial support was provided by NIHGMS (R01 GM103558-03), and gifts from Merck and Amgen. J.J. thanks J. A. Terrett for assistance in preparing this manuscript. Author Contributions J.J. performed and analysed experiments. J.J. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and also prepared this manuscript.
4 | N AT U R E | VO L 0 0 0 | 0 0 M O N T H 2 0 1 5 G2015
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doi:10.1038/nature14885
Alcohols as alkylating agents in heteroarene C–H functionalization Jian Jin1 & David W. C. MacMillan1
Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage1. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of ‘spin-centre shift’2, during which an alcohol C–O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radicalbased alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides3–7, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone. During DNA biosynthesis, ribonucleoside diphosphates are converted into their deoxyribonucleoside equivalents via the enzymatic activity of ribonucleotide reductase (class I–III)8. Crucially, a (39,29)spin-centre shift occurs, resulting in b-C–O scission and elimination of water (Fig. 1a). Considering the efficiency of this mild enzymatic process to cleave C–O bonds to generate transient radicals, we postulated whether an analogous chemical process could occur with simple alcohols, such as methanol, to access radical intermediates for use in challenging bond constructions (Fig. 1b). In the medicinal chemistry community, there is growing demand for the direct introduction of alkyl groups, especially methyl groups, to heteroarenes, given their influence on drug metabolism and pharmacokinetic profiles9. The open-shell addition of alkyl radical intermediates to heteroarenes, known as the Minisci reaction10, has become a mainstay transformation with broad application within modern drug discovery11. Unfortunately, many current methods are limited in their application to late-stage functionalization of complex molecules owing to their dependence on the use of strong stoichiometric oxidants or increased temperatures to generate the requisite alkyl radicals3–6. A photoredox-catalysed alkylation protocol using peroxides as the alkyl radical precursors was recently demonstrated7. Given the state of the art, we questioned whether a general alkylation protocol could be devised in which a broad range of substituents could be installed from simple commercial alcohols under mild conditions. Visible light-mediated photoredox catalysis has emerged in recent years as a powerful technique in organic synthesis that facilitates single-electron transfer events with organic substrates12–14. This general strategy allows for the development of bond constructions that are often elusive or currently impossible via classical two-electron 1
pathways. Recently, our laboratory introduced a new dual photoredoxorganocatalytic platform to enable the functionalization of unactivated sp3 C2H bonds15–17. This catalytic manifold provides access to radical intermediates via C2H abstraction, resulting in the construction of challenging C2C bonds via a radical–radical coupling mechanism. With the insight gained from this dual catalytic system and our recent work on the development of a photoredox-catalysed Minisci reaction18, we questioned whether it would be possible to generate alkyl radicals from alcohols and use them as alkylating agents in a heteroaromatic C–H functionalization reaction (Fig. 1c). While there are a few early reports of alcohols as alkyl radical precursors formed via high-energy irradiation (ultraviolet light and gamma rays)19–21, a general and robust strategy for using alcohols as latent alkylating agents has been elusive. This transformation would represent a direct C2H alkylation of heteroaromatics with alcohols via a spin-centre shift pathway, eliminating H2O as the only by-product. We recognized that this mild alkylating procedure would serve as a powerful and general method in late-stage functionalization, using commercially available and abundant alcohols as latent alkylating agents. A detailed description of our proposed dual catalytic mechanism for the alkylation of heteroarenes with alcohols is outlined in Fig. 2. Irradiation of Ir(ppy)2(dtbbpy)1 (1) (in which ppy 5 2-phenylpyridine, dtbbpy 5 4,49-di-tert-butyl-2,29-bipyridine) will generate the longa PPO
PPO
R
R
O HO
O OH
O
RNR class I
SCS
–H2O
b
H
H
H
HO C H
H H
c
Photoredox R
HO Me
R N
Methanol
H
Organocatalysis
N
–H2O
Methyl adduct
Heteroarene R
SCS
N H
OH
Me
R N H
Figure 1 | Bio-inspired alkylation process using alcohols as spin-centre shift equivalents via a dual catalytic platform. a, DNA biosynthesis occurs via a spin-centre shift (SCS) process, catalysed by ribonucleotide reductase (RNR) class I to generate a carbon-centred radical, after elimination of H2O as a byproduct. b, Alcohols (for example, methanol) as radical intermediates when spin-centre shift allowed. c, Proposed direct installation of alkyl groups using alcohols under mild photoredox organocatalytic conditions.
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RESEARCH LETTER
R
R
N Me
N
11
Methylated heteroarene 12
R
R
NH
SCS
NH
–H+
–H2O
10
9
OH
OH
+ H+ R
SET
NH
Heteroarene 3 IrIV (4) oxidant
*IrIII (2) reductant
OH
Photoredox catalytic cycle
SH
EtO SET
cat. 5
IrIII (1) Photoredox catalyst
Visible light source
8
O
Organocatalytic
Me
HAT
cycle PF6–
O
t-Bu
N N N
t-Bu
Ir N
Ir(ppy)2(dtbbpy)PF6 (1)
S
EtO 6
Me
MeOH Alcohol 7
Methanol as methylating agent
Figure 2 | Proposed mechanism for the direct alkylation of heteroaromatic C–H bonds via photoredox organocatalysis. The catalytic cycle is initiated via excitation of photocatalyst 1 to give the excited state 2. A sacrificial amount of heteroarene 3 oxidizes *IrIII 2 to IrIV 4, which then oxidizes thiol catalyst 5 to generate thiyl radical 6 and regenerate catalyst 1. Thiyl radical 6 then abstracts a hydrogen atom from alcohol 7 to form a-oxy radical 8. Radical 8 adds to heteroarene 3, producing radical cation 9, which after deprotonation forms a-amino radical 10. Spin-centre shift elimination of H2O forms radical intermediate 11. Protonation and reduction by *IrIII 2 delivers alkylated product 12. HAT, hydrogen atom transfer; MeOH, methanol; SET, singleelectron transfer.
lived *Ir(ppy)2(dtbbpy)1 (2) excited state (t 5 557 ns)22. As *Ir(ppy)2(dtbbpy)1 (2) can function as either a reductant or an oxidant, we postulated that 2 would undergo a single-electron transfer event with a sacrificial quantity of protonated heteroarene 3 to initiate the first catalytic cycle and provide the oxidizing Ir(ppy)2(dtbbpy)21 (4). Given the established oxidation potential of Ir(ppy)2(dtbbpy)21 (4) (E1/2red 5 11.21 V versus saturated calomel electrode in CH3CN)22, we anticipated that single-electron transfer from the thiol catalyst 5 (E1/2red 5 10.85 V versus saturated calomel electrode for cysteine)23 to Ir(ppy)2(dtbbpy)21 (4) would occur and, after deprotonation, furnish the thiyl radical 6 while returning Ir(ppy)2(dtbbpy)1 (1) to the catalytic cycle. At this stage, we presumed that the thiyl radical 6 would undergo hydrogen atom transfer with the alcohol 7 (a comparable thiol, methyl 2-mercaptoacetate S–H bond dissociation energy 5 87 kcal mol21 (ref. 24), methanol a-C–H bond dissociation energy 5 96 kcal mol21 (ref. 25)) to provide the a-oxy radical 8 and regenerate the thiol catalyst 5, driven by the polar effect in the transition state26. The polar effect is a remarkable property that enables considerably endergonic C–H abstractions that would not be possible otherwise27. The nucleophilic a-oxy radical 8 would then add to the protonated electrondeficient heteroarene 3 in a Minisci-type pathway to afford the aminyl radical cation 9. The resulting a-C–H bond of 9 is sufficiently acidic to undergo deprotonation to form the a-amino radical 10 (ref. 28). At this juncture, intermediate 10 is primed to undergo a spin-centre shift to eliminate H2O and generate benzylic radical 11. The resulting openshell species would then undergo protonation followed by a second
single-electron transfer event with the excited photocatalyst 2 to regenerate the active oxidant Ir(ppy)2(dtbbpy)21 (4), while providing the desired alkylation product 12. We first examined this new alkylation protocol using isoquinoline and methanol as the coupling partners, and evaluated a range of photocatalysts and thiol catalysts. Using Ir(ppy)2(dtbbpy)PF6 (1) and ethyl 2-mercaptopropionate (5), along with p-toluenesulfonic acid and blue light-emitting diodes as the light source, we were able to achieve the desired C–C coupling to provide 1-methylisoquinoline (15) with a 92% yield (see Supplementary Information). Notably, we observed none of the desired product in the absence of photocatalyst, thiol catalyst, acid or light, demonstrating the requirement of all components in this dual catalytic protocol. In addition, this method requires only weak visible light and ambient temperature to install methyl substituents using methanol as the alkylating agent. With the optimal conditions in hand, we sought to evaluate the generality of this dual catalytic alkylation transformation. As highlighted in Fig. 3a, a wide range of heteroaromatics are methylated under the reaction conditions. Isoquinolines with electron-donating or -withdrawing substituents (such as methyl substituents, esters and halides) are functionalized in excellent efficiencies (15–18, 85–98% yield). Quinolines perform effectively, including those that contain non-participating functionality (19–23, 65–95% yield), in addition to phthalazine and phenanthridine coupling partners (24 and 25, 70% and 93% yield). Moreover, a wide range of pyridine derivatives containing diverse functionality (such as esters, amides, arenes, nitriles and trifluoromethyl groups) can be converted into the desired methylation products in high yield (26–32, 65–91% yield). Next, we sought to investigate the nature of the alcohol coupling partner, as demonstrated in Fig. 3b. A broad array of primary alcohols can effectively serve as alkylating agents in this new alkylation reaction. In contrast to the methylation conditions highlighted above, alcohols in Fig. 3b typically use methyl thioglycolate 13 as the C–H abstraction catalyst. Notably, simple aliphatic alcohols such as ethanol and propanol deliver the alkylated isoquinoline product in high yields (33 and 34, 95% and 96% yield). Steric bulk proximal to the alcohol functionality is tolerated, as exemplified by the presence of isopropyl, b-tetrahydropyran, b-aryl and b-adamantyl substituents (35–38, 87– 92% yield). The presence of an electron-withdrawing trifluoromethyl (CF3) group distal to the alcohol decreases the rate of the reaction; however, using the more electrophilic thiol catalyst, 2,2,2-trifluoroethanethiol (14), can promote the transformation more efficiently, possibly owing to the polar effect on the hydrogen atom transfer transition state (39, 93% yield)26. We found that diols also participate readily in this alkylation protocol (40 and 41, 88% and 81% yield). It should be noted that 1,3-butanediol demonstrates exceptional chemoselectivity and undergoes alkylation exclusively at the primary alcohol site. We speculate that the corresponding a-oxy radical at the secondary alcohol position does not attack the protonated heteroarene owing to its increased steric hindrance. For these alkylating agents with several reactive sites (41, 43 and 44), thiol catalyst 5 is the most effective hydrogen atom transfer catalyst—mechanistic studies are continuing to determine the origin of these differences in catalyst reactivity. Ethers, in the form of differentially substituted tetrahydrofurans, are also competent alkylating agents in this dual catalytic platform (42–44, 72–90% yield). In the elimination step, the tetrahydrofuran ring opens to reveal a pendent hydroxyl group. Interestingly, 3-hydroxytetrahydrofuran and tetrahydrofurfuryl alcohol react regioselectively at the ether a-oxy site distal to the alcohol to afford alkylation products with terminal pinacol motifs. We attribute this exclusive regioselectivity to a subtle influence on C–H bond dissociation energy owing to the inductive influence of the oxygen atoms. The application of these substrates represents an effective method to install vicinal diol motifs that would be inaccessible using traditional oxidative alkylation methods. Finally, the utility of this mild alkylation protocol has been demonstrated by the late-stage
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LETTER RESEARCH 1 mol% photocatalyst 1 R1
HO N
H
O
5 mol% thiol catalyst 5
R2
R1
TsOH, DMSO, Blue LEDs, 23 °C
Heteroarene
R2
N
Thiol cat. 5
F3C
SH
MeO
Me
Alkylated heteroarene
Alcohol
O
SH
EtO
Thiol cat. 13
SH
Thiol cat. 14
a Heteroarenes Me N
N
Me
Me N
Me
16, 91% yield
Me
Me
N
Me
15, 92% yield
Br
CO 2Me
N
Me
17, 98% yield
18, 85% yield
Me
Me
Me
N
21, 93% yield
N
Me
23, 89% yield
Me
CO 2Me
27, 81% yield
Me
b Alcohol
N
26, 82% yield Me
CF 3
CN
Me
N
N
Product
N
Me
N
29a: 2-Me, 65% yield 29b: 2,6-diMe, 12% yield
28, 83% yield
CO 2Me Me
Ph
Ph N
Me
25, 93% yield
24, 70% yield
CONH 2 Me
Me N
Me
Me
Me
20, 95% yield
N
Ph
22, 91% yield
19a: 2-Me, 43% yield 19b: 4-Me, 22% yield
N
Br
N
N
c
Product
Alcohol
Me
Me
31a: 2-Me, 56% yield 30a: 4-Me, 61% yield 30b: 2-Me, 15% yield 31b: 2,6-diMe, 25% yield 30c: 2,4-diMe, 7% yield
N
Me
32, 91% yield
Product
Ether R
HO
N
R
N
N
HO R
33 R = Me 34 R = Et
95% yield 96% yield
N
O Me
Me
OH
90% yield 72% yield
42 R = H 43 R = OH
35, 91% yield
Me
HO
N
N
O
O
HO
OH
OH
44, 77% yield
Me
36, 87% yield
R
O
OH
37, 90% yield
d Medicinal agents N
HO
CF 3
HN
N
HO
CF 3
N
39, 93% yield
38, 92% yield
O
S
N
O
CN
HO
OH
N
OH
HO
N
N OH Me
OH
40, 88% yield
Me
N H
O
Me
Me
Fasudil derivative
41, 81% yield
45, 82% yield
Milrinone derivative 46, 43% yield
Figure 3 | Substrate scope for the alkylation of heteroaromatic C–H bonds with alcohols via the dual photoredox organocatalytic platform. A broad range of heteroaromatics and alcohols are efficiently coupled to produce alkylated heterocycles under the standard reaction conditions (top, generalized reaction). a, A variety of isoquinolines, quinolines, phthalazines, phenanthridines and pyridines are efficiently methylated using methanol as the alkylating reagent. b, A diverse selection of alcohols serve as effective alkylating
agents in this dual catalytic protocol. c, Ethers are also amenable to the transformation; the products are the corresponding ring-opened alcohols. d, Two pharmaceuticals, fasudil and milrinone, can be alkylated using this protocol, demonstrating its utility in late-stage functionalization. Isolated yields are indicated below each entry. See Supplementary Information for experimental details.
functionalization of several pharmaceutical compounds. Using methanol as a simple methylating agent, fasudil, a potent Rho-associated protein kinase inhibitor and vasodilator, can be methylated in 82% yield (product 45). Additionally, milrinone, a phosphodiesterase 3 inhibitor and vasodilator, can be alkylated with 3-phenylpropanol in 43% yield (product 46). Mechanistic studies have been conducted to support the proposed pathway outlined in Fig. 2. Stern–Volmer fluorescence quenching experiments have demonstrated that the *IrIII excited state 2 is
quenched in the presence of protonated heteroarene 3, but not in the presence of the unprotonated heteroarene or thiol catalyst 5, indicating an oxidative quenching pathway (see Supplementary Information). Furthermore, a series of experiments were conducted to investigate the proposed spin-centre shift elimination. After exposing hydroxylated intermediate 47 to the reaction conditions, only a modest amount of the methylated isoquinoline 15 is observed (8% yield, entry 1, Fig. 4a). In the absence of an acid additive, only trace yields of the desired product are formed (2% yield, entry 2, Fig. 4a). However, in 0 0 M O N T H 2 0 1 5 | VO L 0 0 0 | N AT U R E | 3
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RESEARCH LETTER a
2.
1 mol% photocatalyst 1 N
N
3.
2 eq. reductant, 2 eq. acid
47
DMSO, blue LEDs, 23 °C
OH
Entry
Light
Photocatalyst
1
Yes
Yes
2
Yes
3
15
Me
4.
Reductant
Acid
Yield
None Bu3N-HCO2H
TsOH
8%
Yes
None
2%
Yes
Yes
Bu3N-HCO2H
TsOH
60%
4
No
Yes
Bu3N-HCO2H
TsOH
0%
5
Yes
No
Bu3N-HCO2H
TsOH
0%
5. 6.
7.
8.
b
+ e–
N
47 48
N
H
+ e– H
15
9.
49
OH
SCS cleaves alcohol C–O bond
c
1 mol% photocat. 1 N
10.
N
2 eq. TsOH, DMSO
47
OH
blue LEDs, 23 °C
11. 12.
50 65% yield
Figure 4 | Mechanistic studies support spin-centre shift elimination pathway. a, Hydroxymethyl intermediate 47 can be converted to methylated 15 under net reductive conditions after addition of formic acid-tributylamine and p-toluenesulfonic acid (TsOH). b, Deoxygenation of 47 probably proceeds via a spin-centre shift pathway to cleave the alcohol C–O bond. c, In the presence of styrene, 47 is converted to 50, presumably by trapping of radical 49. DMSO, dimethylsulfoxide; LEDs, light-emitting diodes.
13.
14. 15.
16.
17.
Wessig, P. & Muehling, O. Spin-center shift (SCS) – a versatile concept in biological and synthetic chemistry. Eur. J. Org. Chem. 2219–2232 (2007). Minisci, F., Vismara, E. & Fontana, F. Homolytic alkylation of protonated heteroaromatic bases by alkyl iodides, hydrogen peroxide, and dimethyl sulfoxide. J. Org. Chem. 54, 5224–5227 (1989). Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011). Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011). Antonchick, A. P. & Burgmann, L. Direct selective oxidative cross-coupling of simple alkanes with heteroarenes. Angew. Chem. Int. Edn Engl. 52, 3267–3271 (2013). DiRocco, D. A. et al. Late-stage functionalization of biologically active heterocycles through photoredox catalysis. Angew. Chem. Int. Edn Engl. 53, 4802–4806 (2014). Eklund, H., Uhlin, U., Fa¨rnega˚rdh, M., Logan, D. T. & Nordlund, P. Structure and function of the radical enzyme ribonucleotide reductase. Prog. Biophys. Mol. Biol. 77, 177–268 (2001). Scho¨nherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Edn Engl. 52, 12256–12267 (2013). Minisci, F., Bernardi, R., Bertini, F., Galli, R. & Perchinunno, M. Nucleophilic character of alkyl radicals–VI: A new convenient selective alkylation of heteroaromatic bases. Tetrahedron 27, 3575–3579 (1971). Duncton, M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal chemists. Med. Chem. Commun. 2, 1135–1161 (2011). Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011). Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013). Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014). Qvortrup, K., Rankic, D. A. & MacMillan, D. W. C. A general strategy for organocatalytic activation of C–H bonds via photoredox catalysis: direct arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014). Hager, D. & MacMillan, D. W. C. Activation of C–H bonds via the merger of photoredox and organocatalysis: a coupling of benzylic ethers with Schiff bases. J. Am. Chem. Soc. 136, 16986–16989 (2014). Cuthbertson, J. D. & MacMillan, D. W. C. The direct arylation of allylic sp3 C–H bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015). Jin, J. & MacMillan, D. W. C. Direct a-arylation of ethers through the combination of photoredox-mediated C–H functionalization and the Minisci reaction. Angew. Chem. Int. Edn Engl. 54, 1565–1569 (2015). Ochiai, M. & Morita, K. A novel photo-induced methylation of pyrimidines and condensed pyrimidine compounds. Tetrahedr. Lett. 8, 2349–2351 (1967). Stermitz, F. R., Wei, C. C. & Huang, W. H. Imine photoalkylations: quinolone and isoquinoline. Chem. Commun. (Lond.) 1968, 482–483 (1968). Sugimori, A. et al. Radiation-induced alkylation of quinoline derivatives with alcohol. Bull. Chem. Soc. Jpn. 59, 3905–3909 (1986). Slinker, J. D. et al. Efficient yellow electroluminescence from a single layer of a cyclometalated iridium complex. J. Am. Chem. Soc. 126, 2763–2767 (2004). Shaidarova, L. G., Ziganshina, S. A. & Budnikov, G. K. Electrocatalytic oxidation of cysteine and cystine at a carbon-paste electrode modified with ruthenium(IV) oxide. J. Anal. Chem. 58, 577–582 (2003). Escoubet, S. et al. Thiyl radical mediated racemization of nonactivated aliphatic amines. J. Org. Chem. 71, 7288–7292 (2006). Berkowitz, J., Ellison, G. B. & Gutman, D. Three methods to measure RH bond energies. J. Phys. Chem. 98, 2744–2765 (1994). Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999). Cai, Y. & Roberts, B. P. Radical-chain racemization of tetrahydrofurfuryl acetate under conditions of polarity-reversal catalysis: possible implications for the radical-induced strand cleavage of DNA. Chem. Commun. (Camb.) 1998, 1145–1146 (1998). McNally, A., Prier, C. K. & MacMillan, D. W. C. Discovery of an a-amino C–H arylation reaction using the strategy of accelerated serendipity. Science 334, 1114–1117 (2011).
the presence of a stoichiometric reductant and p-toluenesulfonic acid, the elimination of oxygen can be achieved in good efficiency (60% yield, entry 3, Fig. 4a). Crucially, this elimination pathway is shut down in the absence of either light or photocatalyst (entry 4 or 5, respectively, Fig. 4a). Therefore, this net reductive process supports the proposed generation of a-amino radical 48, which could readily form deoxygenated product 15 via a spin-centre shift pathway to b-amino radical 49 (Fig. 4b). This elimination pathway is further corroborated by a series of radical trapping experiments (Fig. 4c and Supplementary Information). In the presence of styrene, hydroxymethyl arene 47 is transformed to adduct 50 (65% yield, Fig. 4c), presumably via the intermediacy of b-amino radical 49. Finally, while we support the mechanism outlined in Fig. 2, we cannot rule out the possibility of a radical chain pathway in which radical 11 abstracts an H-atom from alcohol 7 or thiol catalyst 5. In summary, this alkylation strategy represents the first, to our knowledge, general use of alcohols as simple alkylating agents and enables rapid late-stage derivatization of medicinally relevant molecules. Given the influence on drug pharmacokinetics and absorption, distribution, metabolism and excretion (ADME) properties, this method of installing inert alkyl groups will probably find wide application in the medicinal chemistry community. We have developed a mild and operationally simple alkylation reaction via the synergistic merger of photoredox and thiol hydrogen atom transfer organocatalysis to forge challenging heteroaryl C–C bonds using alcohols as latent nucleophiles. This bio-inspired strategy mimics the key step in enzyme-catalysed DNA biosynthesis via a new spin-centre shift elimination of H2O to generate radical intermediates from simple alcohols.
18.
Received 20 May; accepted 26 June 2015.
Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper. Correspondence and requests for materials should be addressed to D.W.C.M. ([email protected]).
Published online 26 August 2015. 1.
Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 4th edn (Oxford Univ. Press, 2007).
19. 20. 21. 22. 23.
24. 25. 26.
27.
28.
Supplementary Information is available in the online version of the paper. Acknowledgements Financial support was provided by NIHGMS (R01 GM103558-03), and gifts from Merck and Amgen. J.J. thanks J. A. Terrett for assistance in preparing this manuscript. Author Contributions J.J. performed and analysed experiments. J.J. and D.W.C.M. designed experiments to develop this reaction and probe its utility, and also prepared this manuscript.
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